Table 1.

USP15-regulated signaling pathways, target proteins, and their effects on cells.

Pathway	Target Substrate	Mechanism of Action	Effect on Cells	Reference
TGF-β signaling	ALK5	Deubiquitination and stabilization of TβR-I by making a complex with SMAD7 and SMURF2	Enhances the activity of TGF-β signaling and promotes oncogenesis in glioblastoma	[13]
BMP signaling	ALK3	Deubiquitination of type I BMP receptor ALK3 by interacting with BMP inhibitor SMAD6	Enhances BMP target gene transcription in mammalian cells, osteoblastic differentiation in mouse, and embryogenesis in Xenopus	[39]
COP9 signalosome	CRLs	Deubiquitination and stabilization of CRL adaptor proteins and associated substrates	Regulation of cullin activity	[58]
			Regulation of multicellular development and secondary metabolism	[59]
			Protects and stabilizes the components of CRLs for rearrangement and adaptation to altered cellular requirements	[60]
NF-κB signaling	IκBα	Deubiquitination and stabilization of IκBα	Inhibition of NF-ĸB signaling and downstream gene expression	[33]
	NF-κB p65	Inhibition of NF-κBp65 ubiquitination	Induces cell proliferation and inhibition of cell apoptosis in multiple myeloma by activating NF-κB signaling	[68]
	TAB2 and TAB3	Stabilization of TAB2 and TAB3 by inhibiting their proteolysis	Potentiates TNFα- or IL-1β-induced NF-ĸB activation and downstream gene transcription	[67]
Wnt/β-catenin signaling	APC	Stabilization of APC in the β-catenin destruction complex	Suppresses Wnt/β-catenin signaling and target gene expression	[35]
	HECTD1	Deubiquitination and stabilization of HECTD1	Tumor suppression in a subset of glioblastoma by attenuating the canonical Wnt pathway	[73]
	β-catenin	Stabilization of β-catenin by inhibiting degradation	Osteoblast differentiation and bone formation	[74]
p53 signaling	MDM2	Deubiquitination and stabilization of MDM2	Downregulation of p53 along with its target genes and cancer cell survival	[34]
	MDM2 via TIFAB	Increases the deubiquitination and stabilization of MDM2, which is boosted by TIFAB	Suppresses p53 activity in stressed and malignant hematopoietic cells	[80]
	E6	Increases E6 protein stability	Upregulation of E6 oncoproteins may facilitate cancer progression in HPV-infected cells	[82]
	p53	Binding and stabilization of p53	TGF-β signaling-mediated stabilization of p53 through increased USP15 translation that suppresses the early stages of cancer progression	[84]
IGF signaling	IRS-2	Binding to and antagonizing of IRS-2 ubiquitination	Regulation of cancer cell progression by fine-tuning of IGF-induced growth-promoting activity	[87]
Immune signaling	TRIM25	Deubiquitination and stabilization of TRIM25	Promotes antiviral innate immune responses	[91]
Nrf2–Keap1 signaling	Keap1	Deubiquitination of Keap1 and enhancement of the Keap1–Cul3–E3 ligase complex stability	Promotes Nrf2 protein degradation and reduces the Nrf2 target gene expression	[38]